Gay Men's Health Crisis: Treatment Issues - Volume 8 no. 1, March, 1994
Gabriel Torres, M.D. and Derek Link

Prevention of PCP (Prophylaxis)

ACTG 081 compared the use of three agents, trimethoprim- sulfamethoxazole (TMP/SMX; Bactrim or Septra, one double- strength tablet twice daily), dapsone (50mg twice daily) and aerosolized pentamidine (AP; 300mg once monthly) as primary prevention for Pneumocystis carinii pneumonia (PCP) in patients with less than 200 CD4 cells.[1] All patients were maintained on AZT. A total of 842 patients were enrolled at 34 centers between May 1989 and June 1990 and followed for a median of 39.1 months. The median CD4 count at entry was 139.

Subjects who developed side effects to their assigned drug were crossed over to another treatment, but were still counted as part of their original trial arm (this is called an "intent-to-treat" analysis). Patients on TMP/SMX or dapsone who became intolerant were switched to the other oral drug, or to aerosolized pentamidine if they were intolerant to both oral drugs. Patients intolerant to AP were switched to TMP/SMX first, and then to dapsone if intolerant to TMP/SMX.

There was no significant difference in the number of cases of PCP on each of the arms: 42 on TMP-SMX; 48 on dapsone, and 54 on AP. At 24 months, though, the estimated PCP rate was higher (14 percent) for those on AP compared to those who were able to remain on TMP-SMX (9.8 percent) or Dapsone (8.6 percent). This difference was termed "marginally significant" by Dr. Judy Feinberg of Johns Hopkins University and chair of the ACTG Opportunistic Infections Committee. While cases of toxoplasmosis were not significantly different among the three arms: nine on AP, six on dapsone and six on TMP/SMX, most of the cases occurred when patients were switched off the oral agents and on to AP.

Most of the patients (88 percent) assigned to AP never crossed over to one of the oral agents, whereas 50.7 percent of those on TMP-SMX and 41.3 percent of those on dapsone crossed over to another agent because of side effects. Since there were so many cross-over, only 7 percent of the failures on TMP/SMX were actually taking the drug at the time of their diagnosis with PCP, as compared to 75 percent who were taking dapsone and 98 percent who were on AP at the time of their failure.

The most common side effects associated with TMP/SMX and dapsone were rash, fever, nausea and neutropenia. Dose reductions were required for 28.4 percent of patients taking TMP/SMX and 33.3 percent of those taking dapsone. The median time to AZT discontinuation was seventeen months on AP, compared to 13.7 months on dapsone and 14.6 months on TMP/SMX. Therefore patients on AP could remain on AZT longer than those on oral regimens, probably because of fewer hematologic side effects.

Significantly, a subgroup analysis found that in patients with less than 100 CD4 cells, aerosolized pentamidine was significantly less effective than TMP/SMX or dapsone, while the three drugs were equivalent among those with more than 100 CD4 cells. Researchers concluded that, in terms of PCP prevention, systemic prophylaxis with an oral drug was superior in preventing first episodes of PCP, especially among patients with low CD4 cell counts (less than 100), although AP is better tolerated and has fewer side effects that require discontinuation of therapy.

Many clinicians believe that the dose of TMP/SMX used in the study (one double strength tablet twice daily) may be higher than necessary for those who have not previously had PCP. One double-strength tablet per day or three times weekly may reduce toxicities and enable more people to use the drug. A previously published ACTG study showed that one double strength tablet of TMP/SMX per day was 3.5 times more effective than aerosolized pentamidine in preventing second or subsequent episodes of PCP, as well as bacterial infections.[2] In addition, a Dutch study recently showed that one single-strength TMP/SMX tablet was as effective and less toxic than one double-strength per day in preventing first episodes of PCP.[3]

A large CPCRA study, which is still ongoing, is comparing one double strength TMP/SMX tablet daily versus three times weekly in the prevention of PCP and toxoplasmosis. The CPCRA study plans to enroll 2500 participants in order to definitively decide the best dose of TMP/SMX. Other new studies will be comparing atovaquone (Mepron) suspension to dapsone or aerosolized pentamidine in patients that are intolerant to TMP/SMX.

PCP and Access to Care

A research team from the University of Rochester examined hospital records from three cities during the period 1987-90 to assess the impact of access to medical care on PCP-related hospitalizations. Access to medical care was defined as recent use of antiretroviral and/or PCP medication, non- emergency room hospital admission, and medical insurance coverage. Patients on HIV/PCP medications prior to hospitalization had more advanced disease and were sicker than patients who did not receive prior treatment. However, patients with access to care had shorter hospital stays, less use of intensive care units (ICUs), fewer bronchoscopies, and were no more likely to die during the hospitalization. The authors conclude that "appropriate treatment can both conserve resources and improve heath outcomes."[4]

Prevention of Fungal Infections

ACTG 981, a "nested" study within the larger ACTG 081, compared fluconazole (200mg daily) or clotrimazole (Mycelex) troches (10 mg five times daily) for prevention of invasive fungal infections. Invasive fungal infections include cryptococcosis (a fungal infection usually affecting the brain or the lungs), histoplasmosis (an infection found predominantly in the mid-West and the Caribbean), or aspergillus (a fungus which causes pneumonia in neutropenic patients).

The randomized, placebo-controlled study enrolled 428 patients at 29 sites. Median follow-up was 35 months.[5] Very few women (less than 5 percent) were enrolled in the study. The rate of invasive fungal infections was 10.9 percent for the clotrimazole arm compared with 4.2 percent in the fluconazole arm. There were only two cases of cryptococcosis in the fluconazole group versus fifteen in the clotrimazole group. So-called non-invasive fungal infections such as oral and esophageal candidiasis (thrush), fungal infections of the skin and vaginitis were more common among those who received clotrimazole troches. Survival was equal in the two groups; most of the invasive fungal infections occurred in participants with CD4 counts less than 50. Nausea and abdominal pain were more common among those who received fluconazole, although severe toxicities were equally common among both groups. Compliance with fluconazole was significantly better than with clotrimazole, probably due to less frequent dosing of fluconazole and to the poor taste of the Mycelex troches.

There is some concern that the use of fluconazole for preventing fungal infections can create organisms that are resistant to the drug, thus requiring the use of the far more toxic, amphotericin B, in the event that fluconazole resistant thrush develops. Unfortunately, this study did not measure rates of fluconazole resistance. Nevertheless, the study researchers concluded that fluconazole can be effective in preventing fungal infections and should be considered in persons with low CD4 counts. Dr. Feinberg told Treatment Issues that most of the invasive fungal infections occurred in those with below 50 CD4 cells, and even 25 CD4 cells.[6] Therefore, according to Dr. Feinberg the central issue is determining whether the benefits of fluconazole prophylaxis will outweigh the risk of resistance. A placebo-controlled study of fluconazole sponsored by the CPCRA has just finished enrolling over 400 women to determine if the drug is effective in preventing vaginal candidiasis. A parallel resistance study is being conducted to determine whether fluconazole prophylaxis predisposes to resistant organisms in this study.

At ICAAC, azole-resistant Candida (thrush) also received considerable attention. A study from the University of Bristol in the United Kingdom prospectively examined the effect of continuous long-term or intermittent fluconazole therapy compared with no anti-fungal therapy on Candida susceptibility in 66 HIV-positive people. Samples of candida from 27 patients who did not receive fluconazole all remained fluconazole- and ketaconazole-sensitive. Eighty-three percent of isolates from the fourteen patients who received intermittent treatment remained fluconazole-sensitive; 98 percent remained ketaconazole-sensitive. In 25 patients on continuous treatment, 40 percent of isolates were fluconazole-resistant and nine percent were also ketaconazole-resistant. The authors suggest that physicians use care in prescribing fluconazole for fungal prophylaxis, stating that this study "highlights the importance of appropriate prescribing practices."[7]

A French study examined Candida susceptibility in 154 patients who received a variety of fungal prophylaxis regimens (ketaconazole, oral amphotericin B, or fluconazole) or no fungal prophylaxis. The researchers found Candida albicans by culture swab or clinical oral candidiasis as frequently in patients receiving prophylaxis as in those without prophylaxis. Patients receiving prophylaxis were more likely, however, to have a C. tropicalis, C. glabrata, and C. Krusei by culture swab. These species of Candida are often fluconazole-resistant and difficult to treat. The researchers conclude that "continuous (fungal) prophylaxis is questionable."[8]

Prevention and Treatment of MAC

Researchers with the Rifabutin Study Group examined the occurrence of Mycobacterium avium complex (MAC) bacteremia in the placebo arm of the rifabutin prophylaxis study. The 571 patients who participated in the study had AIDS and a median CD4 count of 37. After 313 days of follow-up, 102 (17.9 percent) developed MAC bacteremia. Bacteremic patients were more likely to develop fevers, night sweats, and rigors than non-bacteremic patients. Fatigue and abdominal pain were not more common in bacteremic patients.[9]

In a meeting with activists, Pfizer, Inc., a New York-based drug company, provided information about ongoing studies of azithromycin for the prevention and treatment of MAC.[10] Azithromycin is an antibiotic which is already approved for non-AIDS related indications. An ongoing MAC prophylaxis trial is examining azithromycin (1200mg weekly) versus rifabutin (450mg daily) versus the combination in 568 MAC bacteremic patients. So far, eighteen patients have developed MAC (at mean CD4 count of 16) and 27/568 (5 percent) have discontinued the trial due to side effects. Another MAC prophylaxis trial is comparing 1200mg per week of azithromycin versus placebo. Trial 148 examined azithromycin as a treatment for MAC (600mg versus 1200mg per day). A total of 89 patients were enrolled, and 63 have completed the study. There was no statistical difference in clinical response between the two doses but a trend toward worse response in the high dose group. Reductions in MAC bacteremia were similar at both doses. The higher dose was not as well tolerated and was associated with more cases of gastritis, nausea, and discontinuation of treatment. Pfizer has concluded that 600mg of azithromycin is as good microbiologically as 1200mg in the treatment of MAC and much less toxic. The company is currently comparing two doses of azithromycin (250mg daily and 600mg daily) plus ethambutol (800mg daily) versus clarithromycin (500mg daily) plus ethambutol in 300 patients with MAC.

Hospital-Acquired Infections

Nosocomial (hospital-acquired) infections are a significant threat to all hospitalized patients, including those with HIV. A joint CDC-Veterans Affairs study group prospectively investigated nosocomial infections in a group of 2,635 HIV- infected patients. In total, the study included 3,268 inpatient hospital admissions across five VA medical centers. Two hundred eighty-seven nosocomial infections were identified: 39 percent primary bloodstream infections, 20 percent urinary tract infections, fourteen percent pneumonias, and 27 percent in other sites. Most blood stream infections (65 percent) were associated with the use of central catheter lines. [11]

Another presentation extends these observations. One hundred thirteen nosocomial or community-acquired blood stream infections were examined in a group of 769 HIV-infected patients followed at the New York VA Medical Center. Most nosocomial blood stream infections (86 percent) were associated with central lines. In contrast, only 11 percent of community acquired blood stream infections were associated with the use of central lines.[12]

Pseudomonas aeruginosa (PA) is a bacteria which can cause serious, life-threatening infections in HIV-infected people, according to a report from Cornell University researchers. Forty-two cases of PA, which occurred between 1986 from 1992, were examined. Risk factors for PA infection included: central venous catheters, use of aerosolized pentamidine, corticosteroid use, and ganciclovir use. Neutropenia, antibiotic use, smoking, age, race, sex, and history of intravenous drug use were not associated with increased PA risk. Most PA infections occurred outside of the hospital, although 90 percent of patients who developed PA had been hospitalized within the previous three months. Interestingly, most PA infections occurred between July and September. PA infection recurred in eight of twenty patients who survived an initial episode. Median survival after infection was 80 days. Mortality due to PA was 37 percent (19 percent in patients treated with appropriate antibiotics, 62 percent in patients inappropriately treated).[13]

Cryptosporidiosis: Another Drug Fails

Rosemary Soave, MD, of Cornell Medical College in New York City, presented a study of oral azithromycin for cryptosporidiosis. The study randomized 90 patients with cryptosporidiosis to receive azithromycin 900mg/day or placebo for three weeks. Differences in bowel movement frequency, parasite shedding in stool, and overall clinical response between the azithromycin and placebo groups were not statistically significant. Azithromycin was poorly absorbed in many patients, according to the investigators. Patients who had detectable serum levels of azithromycin appeared to have a clinical response. A study of intravenous azithromycin should now be considered.[14]

Hepatitis B and HIV

Chronic hepatitis B is not associated with faster progression to AIDS in HIV-infected people, according to data from a study of 863 HIV-infected individuals conducted by the US Air Force. Fifty-two patients had chronic HBV (HBV positive surface antigen). These individuals progressed to AIDS in a mean time of 74 months, compared with 72 months in those without chronic HBV infection.[15]

HBV vaccination should be offered to HIV-infected people who have not already been exposed to the virus, according to a French research team. In a study of 536 HIV-infected people followed for two years, fifteen percent of 210 HBV-negative, non-immunized patients developed HBV-infection. The authors conclude HBV vaccination is indicated in this population and that safer sex practices must also be emphasized.[16]

Foscarnet-Resistant HIV

Foscarnet-resistant HIV has been identified in four CMV retinitis patients treated with foscarnet for greater than three months, according to a report from the National Cancer Institute. Foscarnet-resistant HIV has not been described previously. Interestingly, foscarnet inhibits HIV in the test tube and, in clinical studies of CMV retinitis, has been associated with longer survival than ganciclovir treatment. The authors conclude that "Foscarnet-resistant HIV emerge during extended foscarnet therapy for CMV retinitis implying that foscarnet has anti-HIV activity in vivo. Therapy of opportunistic infections with broad spectrum anti-virals can select HIV-resistant strains, and thus impact on future therapeutic options."[17]

Infections from Tap Water

"Rusty" home tap water and recent plumbing repairs may be a source of Mycobacterium haemophilum infection in HIV-infected people in New York City, according to a preliminary from the CDC. Twenty HIV-infected patients who developed M. haemophilum had a median CD4 count of 20 and were compared with matched controls. Those who developed M. haemophilum were more likely to report "rusty-looking" tap water at home and had plumbing repairs during the previous six months. Interestingly, M. haemophilum requires a high-iron environment to grow. However, the CDC researchers did not obtain samples of the suspected water to confirm that it was, in fact, "rusty."[18]

References:

1 Oral Presentation. 17th ACTG Meeting. Washington, D.C. December 4-6, 1993.

2 Hardy et al. N Engl J Med 1992; 327: 1842

3 Schneider et al. N Engl J Med 1992; 327: 1836.

4 Cohn SE, et al. Abstract 1070. ICAAC 1993. New Orleans, October 17-20.

5 Oral Presentation. 17th ACTG Meeting. Washington, D.C. December 4-6, 1993.

6 Personal Communication. Judith Feinberg. January 11, 1994.

7 Johnson EM, et al. Abstract 741. ICAAC 1993. New Orleans, October 17-20.

8 Chavanet P, et al. Abstract 1081. ICAAC 1993. New Orleans, October 17-20.

9 Gordin F, et al. Abstract 1405. ICAAC 1993. New Orleans, October 17-20.

10 Meeting with researchers from Pfizer, Inc. October 28, 1993. New York City.

11 Stroud L, et al. Abstract 67. ICAAC 1993. New Orleans, October 17-20.

12 Simberkoff M, et al. Abstract 527. ICAAC 1993. New Orleans, October 17-20.

13 Tang TI, et al. Abstract 528. ICAAC 1993. New Orleans, October 17-20.

14 Stroud L, et al. Abstract 67. ICAAC 1993. New Orleans, October 17-20.

15 Meier P, et al. Abstract 1408. ICAAC 1993. New Orleans, October 17-20.

16 Ajana F, et al. Abstract 670. ICAAC 1993. New Orleans, October 17-20.

17 Mayers D, et al. Abstract 1068. ICAAC 1993. New Orleans, October 17-20.

18 Gordin F, et al. Abstract 1405. ICAAC 1993. New Orleans, October 17-20.

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